Parenteral injection refers to the administration of drugs or vaccines via injection under or through one or more layers of skin or mucus membranes of an animal. Standard injections are given into the subcutaneous or intramuscular region of an animal, e.g., a human patient. These deep locations are targeted because the tissue expands more easily, relative to shallow dermal sites, to accommodate the 0.13 cc (ml) injection volumes required to deliver most therapeutic agents.
Generally, injections have been classified into different categories, including (1) solutions ready for injection; (2) dry, soluble products ready to be combined with a solvent just prior to being injected into a patient; (3) dry, insoluble products ready to be combined with a suitable injection medium prior to administration; (4) suspensions ready for injection; and (5) emulsions ready for injection. Such injectable formulations are administered by routes including intravenous, subcutaneous, intradermal, intramuscular, intraspinal, intrasistemal, and intrathecal. The nature of the therapeutic agent quickly determines the route of administration. However, the desired route of administration places constraints on the therapeutic formulation itself. For example, solutions for subcutaneous administration require strict attention to tonicity adjustment in order to avoid irritation to the nerves and tissue in the surrounding area of injection. Likewise, suspensions are not administered directly into the blood stream in view of the potential of insoluble particles blocking capillaries.
In comparison to other dosage forms and routes of administration, injectables possess certain advantages, including immediate physiological action (e.g., via intravenous injection), avoidance of intestinal absorption problems attended with many drugs, and the accurate administration of the desired dose into the blood stream of a patient. However, one of the disadvantages of injectables is the pain and discomfort present at the site of administration associated with certain pharmaceutically active agents, as well as the trauma of having a needle inserted under the skin or into a vein. Clearly, there can be some degree of discomfort for the patient with each injection that is administered.
Biopharmaceutical agents are typically reconstituted into sterile solutions for injection into the subcutaneous or intramuscular space using a large gauge needle, e.g., in the range 18-30 gauge. Pain is caused by the depth of the penetration of the needle, the size “gauge” of the needle, the large volume of injection, and the diffusion of drug away from the site of injection, among other things. In addition to problems with administration of injectables due to pain associated with the same, there are other draw backs of current practices with respect to injections. For example, many protein and sustained release drugs require reconstitution immediately prior to administration. Dosing of drugs can be inflexible and inaccurate. Further, many formulations need to be refrigerated in order to protect the drugs from degrading hydrolysis reactions. Further, present administration systems are wasteful in that the injection device retains a significant amount of the drug product. Further, to effect delivery of the necessary dose required, an injectable formulation typically must be concentrated and stabilized. Standard injections are given in the liquid form. Products that are sold as liquids or as lyophilized powders require reconstitution in an aqueous carrier prior to injection. Many therapeutic protein and vaccine products are produced in a dry, solid form to promote stability while on the shelf. These formulations are diluted prior to injection in sterile water, phosphate buffer solution, or isotonic saline.
PCT Publication No. WO 2004/057959, which is hereby incorporated by reference to the same extent as though fully replicated herein, describes an auto-injection device that can be used to administer ultraconcentrated biopharmaceutical agents by injection in the form of a paste or suspension. The relatively low volume of these formulations facilitates a minimally invasive, low-pain administration by injection into the epidermal, dermal or subcutaneous layer of the skin. While this constitutes a significant advance in the art, the paste suspensions may require various surfactants and other ingredients, for example, antioxidants to stabilize the biopharmaceutical agents and surfactants to improve the injectable nature of the formulation. Other auto-injection devices include auto-injectors as described, for example, in U.S. Pat. No. 5,092,843, which issued to Monroe et al. These devices deliver biopharmaceutical agents by injection in that is assisted by the power stroke of a piston.
Despite the advances that have been made with injectables, there is needed in the art simplified methods and formulations that provide dosing of therapeutic peptides and other biopharmaceuticals in a concentrated dose via intracutaneous injection into the epidermal, dermal or subcutaneous layer of the skin. Further, it would be beneficial if such formulations were provided in a stabilized platform that does not require reconstitution or refrigeration. Still further, it would be beneficial if such formulations could be administered in a manner that substantially avoids pain associated with the injection of such formulations.